KR20240010065A - Pharmaceutical composition comprising empagliflozin co-crystal - Google Patents

Abstract

The present invention provides a pharmaceutical composition containing a co-crystal of empagliflozin and having a moisture content of 3% or less in the composition, and a pharmaceutical preparation containing the same. The pharmaceutical composition of the present invention is capable of maintaining the co-crystal of empagliflozin and has the effect of preventing browning that occurs when lactose is used in the formulation of the empagliflozin co-crystal. In addition, the pharmaceutical preparation of the present invention can maximize the wetness blocking effect by including a coating base that can block the wettability of the empagliflozin co-crystal.

Description

Pharmaceutical composition comprising empagliflozin co-crystal {Pharmaceutical composition comprising empagliflozin co-crystal}

The present invention relates to a pharmaceutical composition containing empagliflozin co-crystal and a pharmaceutical preparation containing the same.

Empagliflozin is a SGLT2 (Sodium Glucose Co-Transporter 2) inhibitor drug represented by the following formula (I), and is commercially available as a treatment for type 2 diabetes and a treatment for chronic heart failure. It is also under development.

[Formula I]

Empagliflozin can be used in free base crystalline or amorphous form as the main ingredient, and co-crystals can also be used.

It was discovered that the structure of the empagliflozin co-crystal is difficult to maintain due to the structural characteristics of the co-crystal and external factors (moisture, temperature, etc.), and in particular, it is difficult to maintain the structure due to moisture. If the empagliflozin co-crystal is not maintained, its physicochemical properties may change and affect absorption in the body, so development of pharmaceutical technology that can maintain the co-crystal is necessary.

In addition, during the formulation process of the empagliflozin cocrystal, browning was observed when lactose, a diluent used in the reference drug and one of the most commonly used diluents in formulations, was used. Therefore, pharmaceutical technology that can improve these problems is also needed.

Republic of Korea Patent Publication No. 10-2008-0015424

The object of the present invention is to provide a pharmaceutical composition capable of maintaining the empagliflozin co-crystal form.

Another object of the present invention is to provide a pharmaceutical composition that prevents the browning phenomenon that occurs when lactose, which is a diluent used in reference drugs and one of the most commonly used diluents in formulation, is used in the formulation of empagliflozin co-crystal. It is done.

Another object of the present invention is to provide a pharmaceutical formulation containing a coating agent capable of blocking the wettability of the empagliflozin co-crystal.

This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Additionally, the scope of the present invention cannot be considered limited by the specific description described below.

According to one embodiment of the present invention, the present invention provides a pharmaceutical composition containing empagliflozin co-crystal and having a moisture content of 3% or less in the composition.

In the pharmaceutical composition of the present invention, the empagliflozin co-crystal may be included in an amount of 0.1 to 30% by weight, preferably 0.3 to 20% by weight, based on the total composition. Additionally, the empagliflozin cocrystal may be empagliflozin L-proline.

In the pharmaceutical composition of the present invention, the moisture content in the composition is minimized to 3% or less, so that the structure of the empagliflozin co-crystal form can be maintained. In other words, the more the moisture content is minimized, the more desirable it is, and accordingly, there is a technical feature at the upper limit of the numerical range. However, the moisture content may be 0.1 to 3%.

In the pharmaceutical composition of the present invention, an organic solvent containing less than 5% moisture may be used as a binding solvent in the joining process with the empagliflozin co-crystal for preparing the pharmaceutical composition. Specifically, the organic solvent may be anhydrous ethanol (for example, USP 99.5% or higher) or isopropyl alcohol, but any organic solvent containing less than 5% moisture may be used without limitation.

In the pharmaceutical composition of the present invention, the pharmaceutical composition may further include one or more additives selected from the group consisting of diluents, binders, disintegrants, and lubricants.

In the pharmaceutical composition of the present invention, the diluent may not contain lactose. Additionally, the diluent may include sugar alcohol. For example, the sugar alcohol may be one or more selected from the group consisting of mannitol, sorbitol, erythritol, xylitol, lactitol, and maltitol, and mannitol is preferably used. When the sugar alcohol is used instead of lactose as a diluent, the browning phenomenon observed when the formulation includes lactose can be prevented. Meanwhile, the sugar alcohol may be included in an amount of 30 to 70% by weight, specifically, 40 to 60% by weight, based on the total composition.

In addition, the diluents include microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, silicified microcrystalline cellulose, dextrose, dextrose, fructose, and sucrose. It may further include one or more selected from the group consisting of, but is not limited thereto. Meanwhile, other diluents added in addition to sugar alcohol may be included in an amount of 10 to 40% by weight, specifically, 15 to 30% by weight, based on the total composition.

In addition, the binder is selected from the group consisting of hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, starch, pregelatinized starch, carbomer, xanthan gum, polyvinyl alcohol, vinylpyrrolidone, and povidone. It may be 1 or more, but is not limited thereto. Meanwhile, the binder may be included in an amount of 0.5 to 10% by weight, specifically, 1 to 4% by weight, based on the total composition.

In addition, the disintegrant is a group consisting of crospovidone, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, sodium croscarmellose, and low-substituted hydroxypropyl cellulose. It may be one or more selected from, but is not limited thereto. Meanwhile, the disintegrant may be included in an amount of 2 to 20% by weight, specifically, 4 to 12% by weight, based on the total composition.

Additionally, the lubricant may be one or more selected from the group consisting of talc, colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, sodium lauryl sulfate, and glyceryl behenate, but is not limited thereto. Meanwhile, the lubricant may be included in an amount of 0.1 to 10% by weight, specifically, 0.5 to 4% by weight, based on the total composition.

According to another embodiment of the present invention, the present invention provides a pharmaceutical preparation comprising the pharmaceutical composition of the present invention.

In the pharmaceutical preparation of the present invention, the preparation may be a tablet, capsule, pellet, granule or powder, and preferably may be a tablet. Additionally, the tablet may be a film-coated tablet.

In the pharmaceutical preparation of the present invention, especially the film-coated tablet, the coating base may not contain hypromellose. Instead, polyvinyl alcohol (PVA) may be included in the coating base. Empagliflozin L-proline has a problem with strong moisture absorption, and a polyvinyl alcohol coating base can be used to block moisture absorption as much as possible.

Meanwhile, the pharmaceutical preparation of the present invention can be used to treat diabetes, diabetic complications, or chronic heart failure. The diabetes may be type 1 diabetes or type 2 diabetes, and preferably type 2 diabetes. Additionally, the diabetes complications may be retinopathy, nephropathy or neuropathy, diabetic foot ulcers, tumors, or macroangiopathy. In addition, the chronic heart failure may be heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF).

Additionally, according to one embodiment of the present invention, the pharmaceutical preparation of the present invention may further include one or more drugs used to treat diabetes, diabetic complications, or chronic heart failure. Specifically, the drugs include biguanide-based drugs, thiazolidinedione (TZD)-based drugs, DPP-IV inhibitors, SGLT2 inhibitors, SGLT1/SGLT2 dual inhibitors, GLP-1 receptor agonists, sulfonylurea (SU)-based drugs, It may be one or more drugs selected from the group consisting of meglitinide analog drugs and alpha-glucosidase inhibitors (AGIs).

The above biguanide drugs, thiazolidinedione (TZD) class drugs, DPP-IV inhibitors, SGLT2 inhibitors, SGLT1/SGLT2 dual inhibitors, GLP-1 receptor agonists, sulfonylurea (SU) class drugs, and meglitinide analog drugs. And examples of drugs belonging to alpha-glucosidase inhibitors (AGI) are:

Biguanide drugs: metformin, etc.;

Thiazolidinedione (TZD) class drugs: lobeglitazone, rosiglitazone, or pioglitazone, etc.;

DPP-IV inhibitors: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin, teneligl. liptin (teneligliptin), anagliptin (anagliptin) or evogliptin (evogliptin), etc.;

SGLT-2 inhibitors: dapagliflozin, canagliflozin, or ipragliflozin, etc.;

SGLT1/SGLT2 dual inhibitors: sotagliflozin, etc.;

GLP-1 receptor agonists: semaglutide, etc.;

Sulfonylurea (SU) class drugs: glimepiride, glibenclamide, gliclazide, or glipizide, etc.

Meglitinide analogue drugs: nateglinide, repaglinide, etc.

Alpha-glucosidase inhibitors (AGIs): such as acarbose, voglibose, or miglitol.

The pharmaceutical composition of the present invention exhibits an effect of maintaining the empagliflozin co-crystal form.

In addition, the pharmaceutical composition of the present invention has the effect of preventing browning that occurs when lactose, which is a diluent used in the reference drug and one of the most commonly used diluents in formulation, is used when formulating the empagliflozin co-crystal. represents.

In addition, the pharmaceutical preparation of the present invention can maximize the wetness blocking effect by including a coating base that can block the wettability of the empagliflozin co-crystal.

Figure 1 shows the XRD results of observing whether the co-crystal is maintained or changed in Experimental Example 1.
Figures 2 and 3 show XRD results observing whether the co-crystal was maintained or changed in Experimental Example 2 (Figure 2: ethanol, Figure 3: isopropyl alcohol).
Figure 4 is a photograph observing whether browning occurs depending on the type of diluent in Experimental Example 3.

Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, these examples and experimental examples are for illustrative purposes only and the scope of the present invention is not limited to these examples and experimental examples.

Experimental Example 1. Test to confirm cocrystal maintenance according to moisture content

The coated tablet of Example 1 was prepared with the composition shown in Table 1 below. The moisture content of Example 1 is 1.6%.

[Table 1]

In addition, coated tablets of Examples 2 and 3 were prepared with the same composition as Example 1 except that the moisture content was adjusted to 2.6% and 2.9%. In addition, coated tablets of Comparative Examples 1 to 3 were prepared with the same composition as Example 1 except that the moisture content was adjusted to 3.2%, 3.6%, and 4.0%.

The results of co-crystal maintenance or change according to water content in Examples 1 to 3 and Comparative Examples 1 to 3 are summarized in Table 2 below.

[Table 2]

As seen in Table 2 and Figure 1 above, the coated tablets of Examples 1 to 3 maintained the empagliflozin co-crystal (L-proline), while the coated tablets of Comparative Examples 1 to 3 contained empagliflozin Changes in the cocrystal (L-proline) were observed.

Experimental Example 2. Test to confirm maintenance of co-crystal according to moisture of organic solvent

The composition of Example 4 was prepared with the composition shown in Table 3 below. When preparing the composition of Example 4, anhydrous ethanol was used in the combined process.

[Table 3]

In addition, the compositions of Comparative Examples 4 and 5 were prepared with the same composition as Example 4 except that the moisture content of the binder was adjusted to 5% and 10%. In addition, the compositions of Example 5 and Comparative Examples 6 and 7 were prepared with the same composition as Example 4, except that isopropyl alcohol was used instead of ethanol and the moisture content of the binder was adjusted to 0%, 5%, and 10%. .

The results of co-crystal maintenance or change in Examples 4 and 5 and Comparative Examples 4 to 7 are summarized in Table 4 below.

[Table 4]

As seen in Table 4 above and Figures 2 and 3, the compositions of Examples 4 and 5 maintained the empagliflozin co-crystal (L-proline), while the compositions of Comparative Examples 4 to 7 contained empagliflozin Changes in rosin cocrystal (L-proline) were observed.

Experimental Example 3. Test to confirm browning phenomenon depending on the type of diluent

The compositions of Example 6 and Comparative Example 8 were prepared using the compositions shown in Table 5 below.

[Table 5]

As confirmed in Figure 4, discoloration was observed in Comparative Example 8 using lactose as a diluent. This is presumed to be a browning phenomenon (Maillard reaction) caused by the reaction between the amine group of L-florine and the reducing sugar of lactose.

On the other hand, no browning phenomenon was observed in Example 6 using mannitol instead of lactose.

Experimental Example 4. Test to confirm wettability according to type of coating base

The coated tablet of Example 7 with a moisture content of 2.3% was prepared with the same composition as Example 1. In addition, the coated tablet of Comparative Example 9 with a moisture content of 2.3% was prepared using the composition shown in Table 6 below.

[Table 6]

The wettability of Example 7 and Comparative Example 9 was compared under accelerated conditions (40±2°C/RH 75±5%, close 6M), and the results are shown in Table 7 below.

[Table 7]

As seen in Table 7 above, in Comparative Example 9 using HPMC as the coating base, the moisture change increased by about 2.2% from 2.3% to 4.5%, while in Example 7 using PVA as the coating base, the moisture change was It was observed that the moisture increased by only about 0.3% from 2.3% to 2.6%. Therefore, in order to block the wettability of empagliflozin L-proline, it is preferable to use PVA as a coating base rather than HPMC.

From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention can be implemented in other specific forms without changing its technical idea or essential features. In this regard, the embodiments described above should be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed as including the meaning and scope of the patent claims described below rather than the detailed description above, and all changes or modified forms derived from the equivalent concept thereof are included in the scope of the present invention.

Claims (10)

A pharmaceutical preparation comprising a pharmaceutical composition containing an empagliflozin co-crystal and having a moisture content of 3% or less in the composition,
The empagliflozin co-crystal is empagliflozin L-proline,
The pharmaceutical preparation is a tablet,
The tablet is a film-coated tablet,
A pharmaceutical preparation containing polyvinyl alcohol and not hydroxypropylmethylcellulose as a coating base.
The pharmaceutical preparation according to claim 1, wherein the moisture content in the composition is 0.1 to 3%.
The pharmaceutical preparation according to claim 1, wherein an organic solvent containing less than 5% moisture is used as a binding solvent in the union process with the empagliflozin co-crystal.
The pharmaceutical preparation according to claim 1, further comprising one or more additives selected from the group consisting of diluents, binders, disintegrants, and lubricants.
The pharmaceutical preparation according to claim 4, which does not contain lactose as a diluent.
The pharmaceutical preparation according to claim 5, comprising sugar alcohol as the diluent.
The pharmaceutical preparation according to claim 6, wherein the sugar alcohol is at least one selected from the group consisting of mannitol, sorbitol, erythritol, xylitol, lactitol, and maltitol.
The pharmaceutical preparation according to claim 1, which is used to treat diabetes, diabetic complications or chronic heart failure.
The pharmaceutical preparation according to claim 8, further comprising one or more drugs used in the treatment of diabetes, diabetic complications or chronic heart failure.
The method of claim 9, wherein the drug is a biguanide-based drug, a thiazolidinedione (TZD)-based drug, a DPP-IV inhibitor, a SGLT2 inhibitor, a SGLT1/SGLT2 dual inhibitor, a GLP-1 receptor agonist, and a sulfonylurea (SU). A pharmaceutical preparation, which is one or more drugs selected from the group consisting of class drugs, meglitinide analog drugs, and alpha-glucosidase inhibitors (AGIs).